Mechanisms of regulated translation control in cancer and its therapeutic implications

项目摘要： 癌基因和肿瘤抑制因子直接劫持细胞的翻译装置， 蛋白质组指导癌症发展的特定步骤。这在分子上是通过 基因表达的调节节点，可以指导癌症的发生和发展。我的实验室一直在 通过产生现代工具和开发第一个遗传功能丧失和获得， 翻译机器的不同组件的鼠标模型，结合新的 基因调控的翻译景观的定量测量，已经导致了一个根本性的变化， 我们对癌症分子起源的理解。在本提案中，我们将利用和扩大我们的 长期的兴趣在翻译控制癌症，以解决三个主要目标，如下：1）什么是 针对癌症中异常翻译控制程序的合成致命相互作用？在这里，我们将 描述了一系列新的合成致死性基因与主要帽结合蛋白eIF4E的相互作用 我们已经发现了癌细胞特有的。例如，我们将阐明一个令人惊讶的遗传相互作用 翻译控制与剪接以及翻译与线粒体蛋白质稳态之间的关系。我们将 将这些发现转化为体内小鼠模型以及异种移植物和患者来源的异种移植物， 这种合成的致命相互作用在人类癌症中的重要性，并通过采用新的 在人类癌症中阻断eIF4E超活化的选择性化合物。2)翻译控制如何链接 到癌细胞的代谢程序由于营养丰富的驱动合成代谢过程，如蛋白质 合成，我们将确定翻译控制如何影响与饮食相关的代谢稳态， 癌症的细胞环境。我们将评估基因和 肥胖相关癌症中eIF4E活性的无偏性调节和无偏性分析 描述eIF4E对血流中循环的代谢信号传导的影响的方法。3)什么 是癌基因引导“癌核糖体”形成的机制？一个从根本 一个尚未回答的问题是，不同的“癌症核糖体”的存在是否可以驱动癌细胞的翻译， 癌症基因组指导癌症发展的特定步骤。我们将建立第一个系统的， 大规模鉴定核糖体组成并研究其对基因调控全基因组影响 在Myc诱导的肿瘤发展的不同阶段。重要的是，核糖体组成的变化可能 提供了一种全新的治疗途径， 致癌基因

PROJECT ABSTRACT: Oncogenes and tumor suppressors directly highjack the cell’s translation apparatus to make their own tailored proteome to direct specific steps in cancer development. This is molecularly achieved through translationally regulated nodes of gene expression that can direct cancer initiation and progression. My lab has been at the forefront of this research by generating modern tools and developing the first genetic loss- and gain-of-function mouse models for distinct components of the translation machinery which, in combination with new quantitative measures of the translational landscape of gene regulation, have led to a fundamental change in our understanding regarding the molecular origins of cancer. In this proposal, we will leverage and extend our long-standing interests in translational control in cancer to address three major goals, as follows: 1) What are the synthetic lethal interactions targeting the aberrant translation control program in cancer? Here, we will characterize a series of novel synthetic lethal genetic interactions with the major cap-binding protein eIF4E that we have discovered specific to cancer cells. For example, we will elucidate a surprising genetic interaction between translational control and splicing as well as translation and mitochondrial proteostasis. We will translate these findings to in-vivo mouse models as well as xenografts and patient-derived xenografts to define the importance of such synthetic lethal interactions in human cancers and target them by employing new selective compounds that block eIF4E hyperactivation in human cancers. 2) How is translation control linked to metabolic programs in cancer cells? As nutrient abundance drives anabolic processes, such as protein synthesis, we will determine how translation control influences metabolic homeostasis linked to diet and the cellular environment in cancer. We will assess the functional consequences of genetically and pharmacologically modulating eIF4E activity in cancers associated with obesity and employ unbiased profiling methods to delineate the impact of eIF4E on metabolic signaling that circulates in the blood stream. 3) What are the mechanisms by which oncogenes direct the formation of “cancer ribosomes”? A fundamentally unanswered question is whether the presence of distinct ‘cancer ribosomes’ may drive translation of the cancer genome to direct specific steps in cancer development. We will establish the first systematic, and large-scale characterization of ribosome composition and study its genome-wide impact on gene regulation during distinct phases in Myc-induced tumor development. Importantly, changes in ribosome composition may offer a completely new therapeutic pipeline to selectively inhibit human ribosomes that translate specific, cancer-causing mRNAs.